The present literature discloses several attempts to provide compounds for the use of modulating the activity of protein kinases. The invention of US 2011/028492 A1, filed on Jul. 26, 2010, by Barsanti et al., provides bipyridyl compounds and derivatives as such and for use as pharmaceutical compounds in medicine. The disclosed structures comprise pyridyl-, pyrazinyl- and triazinyl-pyridines:
wherein A1-A3 represent independently of each other: N or C—R;
On the other hand the invention of WO 2008/079933 A2, filed on Dec. 20, 2007, by NOVARTIS AG, also provides bipyridyl compounds and derivatives as such and for use as pharmaceutical compounds in medicine. The disclosed structures comprise pyridyl-, pyrazinyl- and triazinyl-pyridines:
wherein A1-A4 represent independently of each other: N or C—R;
Due to the fact that the focus of US 2011/028492 A1 and WO 2008/079933 A2 is directed to pyridyl-pyridines, pyrazinyl-pyridines and triazinyl-pyridines both state of the art documents relate to structurally different compounds containing nitrogen heterocyclic groups than disclosed in the present invention so that the compounds disclosed in US 2011/028492 A1 and WO 2008/079933 A2 do not challenge novelty or inventiveness of the compounds disclosed herein.
It is object of the present invention to provide compounds and/or pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially for prophylaxis and/or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases and infectious diseases, as well as compositions comprising at least one of those compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients.
This object is solved by the compounds and/or their pharmaceutically acceptable salts according to independent claim 1, the compounds of the present invention for use as pharmaceutically active agents, the use of the compounds of the present invention for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, cardiovascular diseases, cell proliferative diseases, inflammation, erectile dysfunction and stroke according to independent claim 6, the use of compounds according to the present invention as inhibitors for the protein kinase CDK9.
Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the examples and the drawings.
The novel disubstituted pyridine compounds according to the present invention are defined by the general formula (I)
whereinR1 is
L is a bond or —CR5R6—, —CR5R6—CR7R8—, —CR5R6—CR7R8—CR9R10, —CR5R6—CR7R8—CR9R10—CR11R12;R5—R12 represent independently of each other —H, —CH3, —C2H5, —C3H7, —F, —Cl, —Br, —I;R3 is selected from —H, —NO2, —NH2, —CN, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —O—CH3, —O—C2H5, —O—C3H7, —O—CH(CH3)2, —O—C4H9, —O—CH2—CH(CH3)2, —O—CH(CH3)—C2H5, —O—C(CH3)3, —CR13R14R21, —CR13R14—CR15R16R21, —O—CR13R14R21, —CR13R14—CR15R16—CR17R18R21, —CR13R14—CR15R16—CR17R18—CR19R20R21, —O—CR13R14—CR15R16R21, —O—CR13R14—CR15R16—CR17R18R21, —SO2R22, —CONR23R24, —NR25COR22, —O—CR13R14—CR15R16—CR17R18—CR19R20R21, —NR25SO2NR23R24, —NR25SO2R22, —NR25CONR23R24, —SO2NR23R24, —SO(NR26)R22, —NR23R24;R13—R21 and R29—R32 represent independently of each other —H, —CH3, —C2H5, —C3H7, —C4H9, —F, —Cl, —Br, —I;R26 is —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —C5H11, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —CH(C2H5)2, —C2H4—CH(CH3)2, —C6H13, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —CR13R14R21, —COR28, —CR13R14—CR15R16R21, —CR13R14—CR15R16—CR17R18—CR19R20—CR29R30R21, —CR13R14—CR15R16—CR17R18R21, —CR13R14—CR15R16—CR17R18—CR19R20R21, —CR13R14—CR15R16—CR17R18—CR19R20—CR29R30—CR31R32R21, —COOR28, —R27,R22, and R28 are independently selected from —R27′, —CR13R14R21, —CH3, —C2H5, —C3H7, —CR13R14—CR15R16R21, —CR13R14—CR15R16—CR17R18—CR19R20—CR29R30R21, —CR13R14—CR15R16—CR17R18R21, —CR13R14—CR15R16—CR17R18—CR19R20R21, —CR13R14—CR15R16—CR17R18—CR19R20—CR29R30—CR31R32R21, —CH2Ph; —CH2Ph the phenyl group of which may further be substituted by one, two, three, four or five substituents selected from the group consisting of —CH3, —C2H5, —C3H7, —F, —Cl, —Br and —I;R27, R27′ and R27″ are independently selected from
these C3-C10-cycloalkyl groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of —F, —Cl, —Br and —I;R23, R24, R77 and R78 are independently selected from —H, —CH3, —CR13R14R21, —C2H5, —C3H7, —CR13R14—CR15R16R21, —CR13R14—CR15R16—CR17R18—CR19R20—CR29R30R21, —CR13R14—CR15R16—CR17R18R21, —CR13R14—CR15R16—CR17R18—CR19R20R21, —CR13R14—CR15R16—CR17R18—CR19R20—CR29R30—CR31R32R21, —CR13R14—CR15R16—O—R33, —CR13R14—CR15R16—NR33R34, —CR13R14—CR15R16—CR17R18—NR33R34, —CR13R14—CR15R16—CR17R18—CR19R20—NR33R34, —CR13R14—CR15R16—CR17R18—O—R33, —CR13R14—CR15R16—CR17R18—CR19R20—CR29R30—NR33R34, -Ph, —CH2Ph, phenyl group which may further be substituted by one, two, three, four or five substituents selected from the group consisting of —CH3, —C2H5, —C3H7, —F, —Cl, —Br and —I;—CH2Ph the phenyl group of which may further be substituted by one, two, three, four or five substituents selected from the group consisting of —CH3, —C2H5, —C3H7, —F, —Cl, —Br and —I; orboth residues R23 and R24 together form with the nitrogen atom to which they are attached a azetidine, pyrrolidine, piperidine, piperazine, azepane, or morpholine ring;R33 and R34 represent independently of each other —H, —CH3, —C2H5, —C3H7, —C4H9, —CH2Ph, —COOC(CH3)3, —COOCH3, —COOCH2CH3, —COOCH2CH2CH3, —COOCH(CH3)2, —COOCH2Ph, —COCH3;and R25 is selected from —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5 or —C(CH3)3;R4 is selected from —H, —NO2, —CN, —F, —Cl, —Br, —I, —CR35R36R37, —CR35R36—CR38R39—CR40R41—CR42R43R37, —O—CR35R36—CR38R39R37, —O—CR35R36—CR38R39—CR40R41R37, —CR35R36—CR38R39—CR40R41R37, —O—CR35R36—CR38R39—CR40R41—CR42R43R37, —CR35R36—CR38R39R37, —O—CR35R36—CR38R39—CR40R41—CR42R43—CR44R45R37, —O—CR35R36R37, —O—CR35R36—CR38R39—CR40R41—CR42R43—CR44R45—CR46R47R37, —CR35R36—CR38R39—CR40R41—CR42R43—CR44R45R37, —CR35R36—CR38R39—CR40R41—CR42R43—CR44R45—CR46R47R37, —OCH2Ph, —R27″, —O—R27″,R35—R47 and R62—R74 represent independently of each other —H, —CR48R49R50, —CR48R49—CR51R52R50, —CR48R49—CR51R52—CR53R54R50, —CR48R49—CR51R52—CR53R54—CR55R56R50, —F, —Cl, —Br, —I;R48—R56 represent independently of each other —H, —F, —Cl, —Br, —I;R4 together with R22 or R23 or R24 or R25 may form a group —CH2CH2— or —CH2CH2CH2— if R4 is attached ortho to -L-R3;R2 is
R57 is selected from —H, —OH, —NO2, —CN, —F, —Cl, —Br, —I, —NR60R61, -D-R64, -D-NR60R61, —O-D-R64, —CHO, —CH2OH, —CO—R60, —CH2OR60;D, D′ and D″ represent independently of each other —CR62R63—, —CR62R63—CR65R66—, —CR62R63—CR65R66—CR67R68—, CR62R63—CR65R66—CR67R68—CR69R70—;R60, R61, R75 and R76 represent independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3; -(cyclo-C3H5);x is 0, 1, 2 or 3;B is a bond, -D′-, -E-;E and E′ represent independently of each other —CR62R63—CR65R66—CR67R68—CR69R70—CR71R72—, —CR62R63—CR65R66—CR67R68—CR69R70—CR71R72—CR73R74—;Y is a bond, —O—, —S—, —SO—, —SO2—, —SO2NH—, —NHSO2—, —CO—, —COO—, —OOC—, —CONH—, —NHCO—, —NH—, —N(CH3)—, —NH—CO—NH—, —O—CO—NH—, —NH—CO—O—;R58 is selected from a bond, -D″-, -E′-;R59 is selected from(i) —H, —OH, —OCH3, —OC2H5, —OC3H7, —O-cyclo-C3H5, —OCH(CH3)2, —OC(CH3)3, —OC4H9, -Ph, —OPh, —OCH2-Ph, —OCPh3, —SH, —SCH3, —SC2H5, —SC3H7, —S-cyclo-C3H5, —SCH(CH3)2, —SC(CH3)3, —SC4H9, —NO2, —F, —Cl, —Br, —I, —P(O)(OH)2, —P(O)(OCH3)2, —P(O)(OC2H5)2, —P(O)(OCH(CH3)2)2, —Si(CH3)2(C(CH3)3), —Si(C2H5)3, —Si(CH3)3, —CN, —CHO, —COCH3, —COC2H5, —COC3H7, —CO-cyclo-C3H5, —COCH(CH3)2, —COC(CH3)3, —COC4H9, —COOH, —COOCH3, —COOC2H5, —COOC3H7, —COOC4H9, —COO-cyclo-C3H5, —COOCH(CH3)2, —COOC(CH3)3, —OOC—CH3, —OOC—C2H5, —OOC—C3H7, —OOC—C4H9, —OOC-cyclo-C3H5, —OOC—CH(CH3)2, —OOC—C(CH3)3, —CONR75R76, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHCO-cyclo-C3H5, —NHCO—CH(CH3)2, —NHCOC4H9, —NHCO—C(CH3)3, —NHCO—OCH3, —NHCO—OC2H5, —NHCO—OC3H7, —NHCO—O-cyclo-C3H5, —NHCO—OC4H9, —NHCO—OCH(CH3)2, —NHCO—OC(CH3)3, —NHCO—OCH2Ph, —NR77R78, —SOCH3, —SOC2H5, —SOC3H7, —SO-cyclo-C3H5, —SOCH(CH3)2, —SOC(CH3)3, —SO2CH3, —SO2C2H5, —SO2C3H7, —SO2-cyclo-C3H5, —SO2CH(CH3)2, —SO2C4H9, —SO2C(CH3)3, —SO3H, —SO2NR75R76, —OCF3, —OC2F5, —O—COOCH3, —O—COOC2H5, —O—COOC3H7, —O—COO-cyclo-C3H5, —O—COOC4H9, —O—COOCH(CH3)2, —O—COOCH2Ph, —O—COOC(CH3)3, —NH—CO—NH2, —NH—CO—NHCH3, —NH—CO—NHC2H5, —NH—CO—NHC3H7, —NH—CO—NHC4H9, —NH—CO—NH-cyclo-C3H5, —NH—CO—NH[CH(CH3)2], —NH—CO—NH[C(CH3)3], —NH—CO—N(CH3)2, —NH—CO—N(C2H5)2, —NH—CO—N(C3H7)2, —NH—CO—N(C4H9)2, —NH—CO—N(cyclo-C3H5)2, —NH—CO—N[CH(CH3)2]2, —NH—CO—N[C(CH3)3]2, —NH—C(═NH)—NH2, —NH—C(═NH)—NHCH3, —NH—C(═NH)—NHC2H5, —NH—C(═NH)—NHC3H7, —NH—C(═NH)—NHC4H9, —NH—C(═NH)—NH-cyclo-C3H5, —NH—C(═NH)—NH[CH(CH3)2], —NH—C(═NH)—NH[C(CH3)3], —NH—C(═NH)—N(CH3)2, —NH—C(═NH)—N(C2H5)2, —NH—C(═NH)—N(C3H7)2, —NH—C(═NH)—N(cyclo-C3H5)2, —NH—C(═NH)—N(C4H9)2, —NH—C(═NH)—N[CH(CH3)2]2, —NH—C(═NH)—N[C(CH3)3]2, —O—CO—NH2, —O—CO—NHCH3, —O—CO—NHC2H5, —O—CO—NHC3H7, —O—CO—NHC4H9, —O—CO—NH-cyclo-C3H5, —O—CO—NH[CH(CH3)2], —O—CO—NH[C(CH3)3], —O—CO—N(CH3)2, —O—CO—N(C2H5)2, —O—CO—N(C3H7)2, —O—CO—N(C4H9)2, —O—CO—N(cyclo-C3H5)2, —O—CO—N[CH(CH3)2]2, —O—CO—N[C(CH3)3]2,(ii) an aromatic or heteroaromatic mono- or bicyclic ring selected from2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazolyl, 3-oxazolyl, 4-oxazolyl, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl,
which optionally may be substituted by one or two substituents selected from —F, —Cl, —Br, —I, —OCH3, —CH3, —NO2, —CN, —CF3;(iii) a saturated ring selected from
R79 represents —H, —CH3, —CH2Ph, —COOC(CH3)3, —COOCH3, —COOCH2CH3, —COOCH2CH2CH3, —COOCH(CH3)2, —COOCH2Ph, —COCH3;the group —B—Y—R58—R59 together with one substituent R57 may form a group —OCH2O—, if R57 is attached in position ortho to —B—Y—R58—R59;with the proviso that R59 is not —H, if B, Y and R58 are bonds;and enantiomers, stereoisomeric forms, mixtures of enantiomers, diastereomers, mixtures of diastereomers, prodrugs, hydrates, solvates, acid salt forms, tautomers, and racemates of the above mentioned compounds and pharmaceutically acceptable salts thereof.
The expression prodrug is defined as a substance, which is applied in an inactive or significantly less active form. Once applied and incorporated, the prodrug is metabolized in the body in vivo into the active compound.
The expression tautomer is defined as an organic compound that is interconvertible by a chemical reaction called tautomerization. Tautomerization can be catalyzed preferably by bases or acids or other suitable compounds.
Preferred are compounds having the general formula (I):
whereinR1 represents
in whichL is a bond, —CH2—, —CH2CH2—, or —CF2—, particularly preferred —CH2—;R3 is —SO2NH2, —SO2NH(CH3), —SO2N(CH3)2, —SO2NH(CH2CH2OCH3), —NHSO2CH3, —NHSO2CH2CH3, —NHSO2CH2CH3, —NHSO2CF3, —SO2CH3, —NHSO2NH2, —SO(NH)CH3, —NH2, particularly preferred —SO2NH2;R4 is —H, —CH3, —F, —Cl, or —CF3, particularly preferred —H;R2 is
in which the group —B—Y—R58—R59 is —OCH3, —OCH2CH3, —OCH2CH2CH3, —OCH2CH2CH2CH3, —OCH(CH3)2, —OPh, —OCH2Ph, —OCH2(4-pyridyl), particularly preferred —OCH3;R57 is —H, —F, or —Cl;x is 0, 1, or 2.
In a further aspect of the present invention, the novel compounds according to the general formula (I) represent chiral compounds. The novel compounds according to the general formula (I) represent a racemate, or a S or a R enantiomer or a mixture of isomers.
Preferably R3 represents —NO2, —NH2, —CN, —F, —Cl, —Br, —I, —SO2R22, —CONR23R24, —NR25COR22, —NR25SO2NR23R24, —NR25SO2R22, —NR25CONR23R24, —SO2NR23R24, —SO(NR26)R22, or —NR23R24. More preferably R3 represents —NO2, —NH2, —SO2R22, —CONR23R24, —NR25COR22, —NR25SO2NR23R24, —NR25SO2R22, —NR25CONR23R24, —SO2NR23R24, —SO(NR26)R22, or —NR23R24. Most preferably R3 represents —NO2, —NH2, —SO2R22, —NR25COR22, —NR25SO2R22, or —SO2NR23R24.
It is also preferred if L represents a bond, —CH2—, —CH2CH2—, or —CF2—. More preferably L represents a bond, —CH2—, or —CH2CH2—.
The residue-L-R3 represents preferably —NO2, —NH2, —SO2R22, —CONR23R24, —NR25COR22, —NR25SO2NR23R24, —NR25SO2R22, —NR25CONR23R24, —SO2NR23R24, —SO(NR26)R22, —NR23R24, —CH2—NO2, —CH2—NH2, —CH2—SO2R22, —CH2—CONR23R24, —CH2—NR25COR22, —CH2—NR25SO2NR23R24, —CH2—NR25SO2R22, —CH2—NR25CONR23R24, —CH2—SO2NR23R24, —CH2—SO(NR26)R22, —CH2—NR23R24, —CH2CH2—NO2, —CH2CH2—NH2, —CH2CH2—SO2R22, —CH2CH2—CONR23R24, —CH2CH2—NR25COR22, —CH2CH2—NR25SO2NR23R24, —CH2CH2—NR25SO2R22, —CH2CH2—NR25CONR23R24, —CH2CH2—SO2NR23R24, —CH2CH2—SO(NR26)R22, or —CH2CH2—NR23R24. More preferably the residue-L-R3 represents preferably —NO2, —NH2, —SO2R22, —NR25COR22, —NR25SO2R22, —SO2NR23R24, —CH2—NO2, —CH2—NH2, —CH2—SO2R22, —CH2—NR25COR22, —CH2—NR25SO2R22, —CH2—SO2NR23R24, —CH2CH2—NO2, —CH2CH2—NH2, —CH2CH2—SO2R22, —CH2CH2—NR25COR22, —CH2CH2—NR25SO2R22, or —CH2CH2—SO2NR23R24.
The following general formula are also especially preferred:
wherein -L-R3, —R4, —B—Y—R58—R59 and —R57 have the meanings as defined herein.
Moreover in all general formulas disclosed herein the residue-L-R3 represents more preferably —NO2, —NH2, —SO2R22, —CONHR23, —CON(R23)2, —NHCOR22, —NHSO2NHR23, —NHSO2N(R23)2, —NHSO2R22, —NHCONHR23, —NHCON(R23)2, —SO2NHR23, —SO2N(R23)2, —SO(NH)R22, —NHR23, —N(R23)2, —CH2—NO2, —CH2—NH2, —CH2—SO2R22, —CH2—CONHR23, —CH2—CON(R23)2, —CH2—NHCOR22, —CH2—NHSO2NHR23, —CH2—NHSO2N(R23)2, —CH2—NHSO2R22, —CH2—NHCONHR23, —CH2—NHCON(R23)2, —CH2—SO2NHR23, —CH2—SO2N(R23)2, —CH2—SO(NH)R22, —CH2—NHR23, —CH2—N(R23)2, —CH2CH2—NO2, —CH2CH2—NH2, —CH2—CH2—SO2R22, —CH2—CH2—NHSO2NHR23, —CH2—CH2—NHSO2N(R23)2, —CH2—CH2—NHSO2R22, —CH2—CH2—NHCONHR23, —CH2—CH2—NHCON(R23)2, —CH2—CH2—SO2NHR23, —CH2—CH2—SO2N(R23)2, —CH2—CH2—SO(NH)R22, —CH2—CH2—NHR23, —CH2—CH2—N(R23)2, —CH2—CH2—CONHR23, —CH2—CH2—CON(R23)2, or —CH2—CH2—NHCOR22. In addition it is preferred if the residue-L-R3 is attached in meta-position of the aniline moiety of the general formulas (I), (II), (IV), (V), (VI) and (VIII).
Still more preferably are the compounds of general formula (III)
wherein-L-R3 represents —NO2, —NH2, —NH(CH3), —NH(C2H5), —NH(C3H7), —N(CH3)2, —N(C2H5)2, —N(C3H7)2, —SO2CH3, —SO2C2H5, —SO2C3H7, —CONH2, —CONH(CH3), —CONH(C2H5), —CONH(C3H7), —CON(CH3)2, —CON(C2H5)2, —CON(C3H7)2, —NHCOCH3, —NHCOC2H5, —NHCOC3H7, —NHSO2NH2, —NHSO2NH(CH3), —NHSO2NH(C2H5), —NHSO2NH(C3H7), —NHSO2N(CH3)2, —NHSO2N(C2H5)2, —NHSO2N(C3H7)2, —NHSO2CH3, —NHSO2C2H5, —NHSO2C3H7, —NHCONH2, —NHCONH(CH3), —NHCONH(C2H5), —NHCONH(C3H7), —NHCON(CH3)2, —NHCON(C2H5)2, —NHCON(C3H7)2, —SO2NH2, —SO2NH(CH3), —SO2NH(C2H5), —SO2NH(C3H7), —SO2N(CH3)2, —SO2N(C2H5)2, —SO2N(C3H7)2, —SO(NH)CH3, —SO(NH)C2H5, —SO(NH)C3H7, —CH2—NO2, —CH2—NH2, —CH2—NH(CH3), —CH2—NH(C2H5), —CH2—NH(C3H7), —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—N(C3H7)2, —CH2—SO2CH3, —CH2—SO2C2H5, —CH2—SO2C3H7, —CH2—CONH2, —CH2—CONH(CH3), —CH2—CONH(C2H5), —CH2—CONH(C3H7), —CH2—CON(CH3)2, —CH2—CON(C2H5)2, —CH2—CON(C3H7)2, —CH2—NHCOCH3, —CH2—NHCOC2H5, —CH2—NHCOC3H7, —CH2—NHSO2NH2, —CH2—NHSO2NH(CH3), —CH2—NHSO2NH(C2H5), —CH2—NHSO2NH(C3H7), —CH2—NHSO2N(CH3)2, —CH2—NHSO2N(C2H5)2, —CH2—NHSO2N(C3H7)2, —CH2—NHSO2CH3, —CH2—NHSO2C2H5, —CH2—NHSO2C3H7, —CH2—NHCONH2, —CH2—NHCONH(CH3), —CH2—NHCONH(C2H5), —CH2—NHCONH(C3H7), —CH2—NHCON(CH3)2, —CH2—NHCON(C2H5)2, —CH2—NHCON(C3H7)2, —CH2—SO2NH2, —CH2—SO2NH(CH3), —CH2—SO2NH(C2H5), —CH2—SO2NH(C3H7), —CH2—SO2N(CH3)2, —CH2—SO2N(C2H5)2, —CH2—SO2N(C3H7)2, —CH2—SO(NH)CH3, —CH2—SO(NH)C2H5, —CH2—SO(NH)C3H7, —CH2CH2—NO2, —CH2CH2—NH2, —CH2—CH2—NH(CH3), —CH2—CH2—NH(C2H5), —CH2—CH2—NH(C3H7), —CH2—CH2—N(CH3)2, —CH2—CH2—N(C2H5)2, —CH2—CH2—N(C3H7)2, —CH2—CH2—SO2CH3, —CH2—CH2—SO2C2H5, —CH2—CH2—SO2C3H7, —CH2—CH2—CONH2, —CH2—CH2—CONH(CH3), —CH2—CH2—CONH(C2H5), —CH2—CH2—CONH(C3H7), —CH2—CH2—CON(CH3)2, —CH2—CH2—CON(C2H5)2, —CH2—CH2—CON(C3H7)2, —CH2—CH2—NHCOCH3, —CH2—CH2—NHCO2H5, —CH2—CH2—NHCO3H7, —CH2—CH2—NHSO2NH2, —CH2—CH2—NHSO2NH(CH3), —CH2—CH2—NHSO2NH(C2H5), —CH2—CH2—NHSO2NH(C3H7), —CH2—CH2—NHSO2N(CH3)2, —CH2—CH2—NHSO2N(C2H5)2, —CH2—CH2—NHSO2N(C3H7)2, —CH2—CH2—NHSO2CH3, —CH2—CH2—NHSO2C2H5, —CH2—CH2—NHSO2C3H7, —CH2—CH2—NHCONH2, —CH2—CH2—NHCONH(CH3), —CH2—CH2—NHCONH(C2H5), —CH2—CH2—NHCONH(C3H7), —CH2—CH2—NHCON(CH3)2, —CH2—CH2—NHCON(C2H5)2, —CH2—CH2—NHCON(C3H7)2, —CH2—CH2—SO2NH2, —CH2—CH2—SO2NH(CH3), —CH2—CH2—SO2NH(C2H5), —CH2—CH2—SO2NH(C3H7)2, —CH2—CH2—SO2N(CH3)2, —CH2—CH2—SO2N(C2H5)2, —CH2—CH2—SO2N(C3H7)2, —CH2—CH2—SO(NH)CH3, —CH2—CH2—SO(NH)C2H5, —CH2—CH2—SO(NH)C3H7, and whereinR2 has the meanings as defined herein.
In general formulas (I), (IV), (V) and (VI) it is preferred that R4 represents hydrogen.
Moreover it is especially preferred if the substituent-L-R3 represents —NO2, —NH2, —SO2NH2, —SO2—NH—C(CH3)3, —SO2CH3, —CH2—SO2NH2, —CH2—SO2—N(CH3)2, —CH2—CH2—SO2NH2, —NHSO2CH3, —NHCOCH3, or —CH2—SO2—NH(CH2CH2CH3).
Furthermore it is preferred if R57 represents —NO2, —CN, —F, —Cl, —Br, and it is more preferred if R57 represents —NO2, —F, —Cl, and it is especially preferred if R57 represents —F. Moreover in general formulas (I), (II), (III), (IV), (VI) and (VII) it is preferred if R57 is attached in position 4 of the phenyl residue R2 or in para position to the linkage of the phenyl residue R2 to the pyridyl ring or in meta position to the substituent —B—Y—R58—R59.
The residue —B—Y—R58—R59 is most preferably an alkoxy group with 1 to 4 carbon atoms and more preferably —OCH3, —OC2H5, —OC3H7 or —OC4H9 and most preferably —OCH3.
R2 is preferably 2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, or 6-fluoro-2-methoxyphenyl.
In yet another preferred embodiment of the present invention, the compound according to the general formula (I) is selected from the group of compounds depicted in the following Table 1.
TABLE 1CompoundNo.StructureNomenclatureB14-(2-Methoxyphenyl)-N- phenylpyridin-2-amine C14-(2-Methoxyphenyl)-N-(3- nitrophenyl)pyridin-2-amine C24-(4-Fluoro-2- methoxyphenyl)-N-(3- nitrophenyl)pyridin-2-amine D13-[(4-(2- Methoxyphenyl)pyridin-2- yl)amino]benzenesulfon- amide D2N-(tert-Butyl)-3-[(4-(4-fluoro- 2-methoxyphenyl)pyridin-2- yl)amino]benzenesulfon- amide E14-[(4-(2- Methoxyphenyl)pyridin-2- yl)amino]benzenesulfon- amide F14-(2-Methoxyphenyl)-N-(3- (methylsulfonyl)phenyl)- pyridin-2-amine G13-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenylmethane- sulfonamide G2[3-((4-(2- Methoxyphenyl)pyridin-2- yl)amino)phenyl]methane- sulfonamide G31-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]-N,N- dimethylmethanesulfon- amide H12-[3-((4-(2- Methoxyphenyl)pyridin-2- yl)amino)phenylethane- sulfonamide I1N1-(4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)benzene-1,3-diamine J1N-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]methane- sulfonamide J2N-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]acetamide K11-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]-N- propylmethanesulfonamide
The compounds of the present invention may form salts with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
In the case the inventive compounds bear acidic groups, salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.